The present invention relates to an improved apparatus for effecting patient-controlled infusion of medicaments and is particularly applicable to the delivery of medicaments which may be absorbed across dermal and mucosal surfaces such as the respiratory tract, the nasal mucosa, the sublingual area, the ocular surface, intravaginal mucosa or intrarectal mucosa.
It has been recognised for some time that patient controlled medicament delivery (PCDD) as in the case of patient controlled analgesia (PCA) is desirable in many situations. Before the advent of patient controlled medicament delivery, therapeutic treatments relied upon periodic injections of medicaments such as natural and synthetic opioids by a physician or nurse. This has the disadvantage that for most of the time the patient""s medicament level may be significantly above or below the optimum.
PCDD improved on the prior art by enabling the infusion of small quantities of medicaments at regular intervals as perceived to be required by the patient. However, to date PCDD has been effected by sophisticated electronic pump systems which have a number of disadvantages:
(a) They are expensive;
(b) They are complex and require skilled maintenance; and
(c) They are capable of administering an overdose as a result of machine failure or of operator error in setting up; a number of deaths from this cause have been reported.
Recently mechanical PCDD pumping systems have been developed to ameliorate some of the disadvantages attendant with prior art devices. Such devices generally consists of a reservoir and a pumping assembly that contains a dose chamber which takes a predetermined amount of time to fill. These pumps have the disadvantage that filling of the dose chamber in the pumping assembly may take a long time and filling of the last portion of the dose chamber may be extremely slow. Moreover, if patients activate mechanical PCDD pumping systems prior to complete filling of the fluid dose chamber they may receive an excess of medicament. Thus, physicians may have no means of controlling the total amount of medicament delivered to a patient, leading to possible medicament overdosing by the patient.
Physicians generally associate the term xe2x80x9clockoutxe2x80x9d with a period of delay between medicament deliveries. They also have an expectation that the dose chamber in the delivery device will be 100% full at the end of each lockout period.
The filling cycle of electronic PCDD pumps is generally immediate. Electronic pumps allow a unit dose of medicament to be delivered and control a time interval where no further doses of medicament can be delivered. When this time interval is completed the patient can activate a switch which indicates his/her desire for another dose. The next unit dose will then be delivered and the next lockout will take effect.
In mechanical PCDD pumps the filling time of the dose chamber is progressive over a period of time which is equivalent to the predetermined lockout period. Typically, a concave filling curve is observed wherein the majority of the dose chamber fills rapidly after medicament delivery/release after which there is a slow and progressive filling of the last portion of the dose chamber. Often the filling time which leads to 100% filling of the dose chamber in such pumps is greater than the lockout period. Thus, a patient who activates the device prior to specified delivery times may obtain less than the absolute dose that is required to fill the dose chamber.
Depending on the type of PCDD pump employed, a patient may also gain significantly greater doses of a medicament than he/she should receive, by using the device at frequent intervals before the dose chamber is completely full. For example, a patient who activates a mechanical PCDD pump once every few minutes for an hour will gain significantly greater amounts of a medicament than they should receive if they use the pump once every 10 minutes over a 1 hour period. This is because the most rapid filling in mechanically controlled PCDD lockout pumps occurs in the first minutes. In some circumstances a patient may, for example, receive more than 200% of the expected dose of medicament if he/she activates the device at shorter time intervals than recommended for medicament delivery. This phenomena has in the past led to patient overdose.
It has been found that by controlling the number of doses of a medicament that a patient receives per hour, it is possible to control many patient symptoms. In particular, patients can control their own symptoms by measuring the symptoms and adding doses of medicaments as required. In such situations physicians would choose the limit which will be an index of medicament safety for a certain dose to be delivered per hour.
The present invention seeks to provide an improved PCDD apparatus which is simple and inexpensive to manufacture and use, and which has a high level of inherent safety.
The present invention provides a delivery device for patient-controlled infusion of a medicament, the delivery device comprising: (i) a reservoir for the medicament; and (ii) a pump which has a predetermined delivery dose, wherein the pump comprises a first conduit which connects the reservoir to a pump chamber, a one-way valve in fluid communication with the first conduit and the pump chamber which permits medicament flow into the chamber but prevents reverse flow therefrom, a second conduit extending from the pump chamber and having a distal end through which the medicament may be released, and a controlling means in fluid communication with said pump chamber and said second conduit, wherein the first conduit is suitably adapted to restrict the flow of medicament into the chamber to a predetermined maximum delivery rate, and wherein the controlling means is adapted to: (a) open only when pressure within the dose chamber exceeds a pre-selected minimum opening pressure for the controlling means; and, (b) is adapted to prevent the reverse flow of medicament and air into the pumping means.
The present invention attempts to minimise the potential for patients to overdose with medicaments by providing a physical time delay between one dose and the next. This delay is created as a working interrelationship between the first conduit, the pumping means and the controlling means. The first conduit restricts the passage of medicament into the dose chamber thereby providing the dose chamber with a predetermined filling time. In combination the controlling means retards the release of medicament from the dose chamber until a suitable opening pressure (driving force) can be generated in the dose chamber to open the controlling means. Thus, an efficient lockout may be created whereby a patient is prevented from obtaining additional doses of a medicament from the delivery device until the chamber contains a suitable dose of spray to treat said patient""s ailment.
The first conduit is preferably a fine calibre tube which has a very narrow bore and which limits the filling time of the dose chamber to between 1 minute and 12 hours. The desired time delay for filling the dose chamber would depend on a variety of factors such as the concentration of medicament to be delivered by the delivery device, the physical properties of the medicament, the delivery route, the delivery volume and the number of times that the medicament is to be delivered per day. Preferably, the time delay is between 1 and 60 minutes with 10 to 20 minutes being optimal. For example, the time delay may be 15 minutes.
Any fine calibre tubing that is able to limit the flow rate of medicament into the dose chamber to a desired fill time may be used in the invention. Such a tube and a method for producing it are described in co-owned international patent application WO88/02637. Preferably the tube is 1 to 700 cm in length is substantially resistant to kinking and has a lumen diameter of about 0.001 mm to 0.2 mm. For example, nasal spray apparatuses for the delivery of fentanyl which employ fine calibre tubing that have a lumen diameter in the range of 0.003 of an inch (0.025 mm) and a length of approximately 9 cm give a filling time of approximately 5 minutes with a dose chamber of 0.2 ml (200 xcexcl).
Preferably the fine calibre tubing is connected to the pumping means by a releasable engaging means. The fine calibre tubing employed in the invention has a fine calibre bore which makes it difficult to prime the apparatus. Accordingly the tubing should be separable from the pumping means to facilitate priming and or the attachment of other fine calibre tubings with alternative specifications. Preferably, the flow control tubing is also anchored to the base of the medicament reservoir to ensure that the orifice in the fine calibre tubing through which medicament flows is in constant contact with the medicament.
Preferably the controlling means is biased towards the closed position by a resilient biasing means such as a spring. In a highly preferred form of the invention the controlling means may be a one way ball valve or as a two part plunger wherein the parts are biased together by a biasing means and which is opened by separation of the plunger parts.
The controlling means is preferably positioned in conjunction with the second conduit and is activated only under high pressure. For example, the opening pressure of the controlling means should be greater than 760 mmHg so that all fluid leaving the dose chamber leaves under high pressure thus facilitating atomisation of the medicament as it leaves the second conduit. Preferably the controlling means has an opening pressure in the order of 760 mmHg to about 5000 mmHg. In a more preferred form a pressure of about 1000 mmHg to about 3500 mmHg would be a typical opening pressure with about 3000 mmHg being optimal for the controlling means. Any controlling means which opens when a predefined pressure is reached may be used in the invention.
Once fluid has started to move through the controlling means the pressure required to maintain the controlling means open will preferably be much lower than the initial opening pressure. Means for achieving this end are known in the art.
By employing a high pressure controlling means in the pumping assembly it is possible to restrict a patient""s access to small partial doses of medicament present in a delivery device during the phases of most rapid filling. If the controlling means has a high opening pressure, a patient will generally have great difficulty generating suitable opening pressures when the chamber contains a small amount of medicament and a large vacuum. The mechanical pressure required to generate a high opening pressure while pressing a vacuum against a medicament makes it exceptionally difficult, if not impossible, to release any medicament in a suitable form from the pumping assembly unless mechanical assistance is given to the patient""s hand. The abound of mechanical assistance that may be given to the patient""s hand may be controlled by the size, diameter and length of the dose chamber and the configuration of the mechanism that allows pressure to be applied to the device. Means for achieving this end are known in the art.
The effect established by employing a working interrelationship between the fine calibre tubing and the controlling means is characterised by the availability of medicament throughout the lockout period. Post release of medicament from the dose chamber there is a phase of rapid filling of the chamber. Throughout this phase medicament is prohibited from release from the device because there is insufficient pressure in the dose chamber to force open the high pressure controlling means.
As the volume of medicament in the dose chamber increases the pumping means may become capable of generating a suitable pressure to open the controlling means. However, because all of the energy exerted on the medicament is utilised in opening the controlling means there is insufficient positive pressure generated in the dose chamber to drive the fluid through the second conduit. Thus, any medicament released from the device quickly coalesces to form fluid droplets at the apex of the second conduit. Thus, medicament is not released from the device.
As the dose chamber in the device of the present invention becomes about three quarters full the pressure that may be generated therein is sufficient to force the controlling means open and drive fluid through the second conduit. Thus, medicament may be released from the device. However, because most of the energy (driving force) created upon activation of the device is used to open the controlling means the force driving the spray is relatively low. The released spray quickly coalesces as it leaves the dose chamber. Absorption of the medicament into the dermal or mucosa surrounding the region of medicament delivery is retarded because only a small surface area of tissue comes into contact with the medicament. The quantity of medicament absorbed is proportional to the size of the dermal or mucosal surface which is saturated with the medicament.
When the dose chamber becomes full, maximum pressure can be generated in the dose chamber upon compression of the pump. The droplet size of the medicament decreases as the pressure generated in the dose chamber increases. The decreasing size of droplets and increasing size of the spray allows the medicament to reach the whole of the dermal or mucosa surface that is to be saturated by medicament release. Thus, allowing maximum absorption of a unit dose of medicament.
A preferred feature of the present invention resides in the provision of a means for reducing the medicament to fine particles by atomising it or nebulising it as it passes through the second conduit. To achieve this, fluid is preferably pumped under high pressure along the side walls of the second conduit, preferably in a rotary action. Such an action may, for example, be achieved by forming groves in the inner walls of the conduit which facilitate rotary movement of fluid therein. The conduit is preferably made narrow towards its distal end so that fluid rotating around the conduit increases its centrifugal rotation as it converges on the aperture at the distal end of the conduit. The high centrifugal force causes the fluid emerging from the aperture to break into fine droplets.
The droplet size is determined by the rate of flow through the first conduit, the pressure pushing the fluid up the conduit, the amount of rotation that has been achieved as the fluid moves up the conduit, the amount of convergence at the distal end of the conduit as it narrows into the aperture and the viscosity of the fluid itself. If the invention is employed to deliver a nasal spray, the droplet size may be decreased by increasing the opening pressure of the controlling means. An increase in opening pressure of the controlling means also helps to produce a greater time delay.
Any pumping means that is able to draw medicament through a first conduit and discharge a defined volume of it through a second conduit may be used in the delivery device. Preferably the pumping means has a dose chamber into which medicament is drawn and from which it is expelled. The dose chamber preferably defines the volume of medicament that is drawn into and expelled from the pumping means. A dose chamber with a low unit dose size is preferably employed in the pumping means so that manual pressure applied without any levers or complex devices by a patient is capable of generating high pressures inside the dose chamber. This usually means that the chamber must be small and have a small diameter such that a patient may be able to generate pressures above several thousand millimetres of mercury within the dose chamber to open a controlling means. For nasal sprays a typical unit dose size may be 50 to 250 xcexcl.
The pumping means may be of any form that is capable of withdrawing medicament through fine calibre tubing and then displacing it under high pressure through a second conduit. For example, the pumping means may be a syringe-type design having a plunger biased upwardly within the dose chamber by a resilient restoring means wherein depression of the plunger provides the means for volume reduction and displacing the medicament in the dose chamber. Such a pump is described in European patent application EP 0301615 in the name of Elettro Plastica s.r.l.
If, for example, the pump takes the form of a syringe-type pump the delivery device may be actuated by the user to deliver a fixed dose of medicament by applying pressure to the pump plunger. This forces medicament from the dose chamber through the second conduit which preferably atomises/nebulises the medicament as it passes from the delivery device. A resilient restoring means in the dose chamber then returns the plunger to its resting state thereby reforming the dose chamber. This creates a vacuum in the dose chamber which opens the one-way valve and which draws fluid from the reservoir through the first conduit (eg fine calibre tube) re-filling the dose chamber.
For some medicaments a limit of 2-3 doses per day with delays as long as 6 to 8 hours may be required. It will be appreciated that the administration volume and the time delay between deliveries may be varied by altering, for example, the calibre and/or length of the first conduit and the volume in the dose chamber.
If for example, the pumping means is of a syringe-type design the resilient restoring means may be a spring. The return pressure of the spring should be sufficient to push the syringe mechanism up to create a vacuum. Preferably, the spring is arranged in such a way that at the beginning of pressing the syringe plunger, the pressure on the spring is minimal and as the movement continues the spring pressure increases. When the pressure exerted by the spring is significant it may be very difficult for a patient to express the last part of the fluid unless a high opening pressure in the controlling means has been overcome.
Preferably, the return spring on the plunger is relatively short such that the pressure required to activate the device is low when the chamber is full, medium when the chamber is half full and extremely high when the chamber if full of small quantities such as 10 or 20%. When such a spring is combined with a high pressure controlling means it becomes very difficult to deliver a dose from the dose chamber except when it is full to a significant amount. By altering the balance of pressure exerted by the spring pressures on the return spring driving up the plunger and the inertia pressures on the controlling means it is possible to vary control of medicament release from the initial part of the dose chamber so that expulsion of fluid from it becomes impossible until a desired quantity of fluid has entered the dose chamber.
Alternatively the syringe-type pump may be replaced by a balloon or a concertina type pumping mechanism. In these forms activation of the pump may be achieved by compression of the balloon or concertina mechanism to create a pressure change within the dose chamber. The balloon or concertina mechanism is preferably a thick-walled rubber balloon or concertina mechanism with sufficient recovery force to draw medicament from the reservoir through the first conduit.
Preferable the one-way valve is engaged to either the first conduit or is located between the first conduit and the dose chamber. Without the presence of the one-way valve the small volumes involved with nasal sprays and the pressure of the operating system would create a back flow of fluid through the first conduit. The valve may be, for example, spring, ball or elastomeric activated valve.
The second conduit may be of any length or diameter. Preferably its length and diameter are adapted to suit the orifice or dermal region for which medicament delivery is intended. For example, if medicament delivery is intended for the nasal mucosa or the respiratory tract via the nasal cavity then the second conduit may be short and of a suitable diameter to fit the nostril(s) of a patient. Alternatively, if medicament delivery is intended for the rectal or vaginal mucosa then the second conduit may be comparatively longer and of a wider diameter.
The second conduit may also be sheathed. If the conduit is sheathed then the distal end of the sheath must contain at least an orifice through which medicament can pass as it is released from the delivery device. The sheath may be disposable or a permanent fixture engaged with the delivery device. The sheath may also serve as a means for actuating the pump. For example, if the pump is a syringe-type pump the sheath may partially cover the plunger and may have one or more perpendicular extensions which allow the user to depress the plunger. If however, the pump is an elastomeric balloon then the sheath may serve only as a means for protecting the second conduit.
The reservoir employed in the invention may take any form or contain any volume of medicament. Preferably the reservoir is a bottle or collapsible bag which is adapted to engaged the pump and which is capable of holding the length of the first conduit. Medicament may fill the reservoir or alternatively the reservoir may contain a collapsible bag which holds the medicament.
If the reservoir is in sealing engagement with the pump, there may be provided in the wall of the reservoir one or more means for introducing a medicament into the reservoir. If the reservoir is provided with a delivery portal for introducing medicament into the apparatus, there is preferably provided a means for trapping gases to prevent air inadvertently introduced at the injection site from reaching the reservoir. Alternatively, a release portal may be provided for removing from the system air either introduced inadvertently or in the initial purging of the system.
In an embodiment of the invention the reservoir may be connected to the delivery device via a fluid control system, comprising: (i) a second reservoir which holds a small number of medicament doses which is located between the end of the flow control tubing and the delivery device; (ii) a fluid delivery means interposed between the reservoir and the second reservoir; and (iii) a high pressure activated valve with an opening pressure above atmospheric pressure which is interposed between the fluid delivery means and the second reservoir, wherein the fluid delivery means is capable of drawing medicament through the flow control tubing, is capable of holding a volume of medicament equivalent to the volume held by the second reservoir and is capable of delivering that medicament across the a high pressure activated valve to the second reservoir. A typical opening pressure for the high pressure activated valve would be above 800 mmHg ensuring that even with a full vacuum pressure transferred to the valve, that no fluid will flow cross the valve as the opening pressure is above atmospheric pressure (760 mmHg). In this embodiment the maximum number of doses that can be delivered to the patient is defined by the number of doses held in the second reservoir.
Any fluid delivery means may be used in this embodiment of the invention. For example the fluid delivery means may be an electronic or non electronic pump system or an aspirating syringe etc. If for example, the fluid delivery means is an aspirating syringe and is attached to the reservoir by flow controlling tubing the time for filling the aspirating syringe is controlled by the rate of flow across the flow control tubing. Once the aspirating syringe is full, it may be activated to discharge its contents across the high pressure valve to the second reservoir. The delivery device can then be used to withdraw medicament from the second reservoir to fill the dose chamber prior to delivery to a patient without the need for flow control tubing between the delivery device and second reservoir. The number of doses available to the patient is determined by the number of doses in the second reservoir. Preferably a patient is able to re-prime the second reservoir at a rate controlled by the flow control tubing which controls the rate of fill of the dose chamber. In this embodiment a patient could delivery 3, 4, 5, 6 or whatever number of doses are necessary in order to get the desired clinical effect but the dose number would be limited by the volume of the small reservoir.
In an alternative embodiment the main reservoir may be pressurised. (ie, a spray can). Fluid is then pushed through the flow control tubing to the unit dose reservoir.
In another embodiment of the present invention there may be provided a secondary delivery control assembly which is releasable engaged to the second conduit, to facilitate control of fluid delivery. The secondary delivery control assembly comprising (i) a second delivery chamber, (ii) a return tube to the reservoir and (iii) an intravenous delivery line. The return tube preferably extends from the second delivery chamber to the reservoir bottle and facilitates the return of medicament released into the second delivery chamber which is incapable of entering the intravenous delivery line. Within the housing of the second delivery chamber there is provided an air filter to remove trapped air and a delivery portal within which there is located a second pressure activated controlling means. Connected to the delivery portal in a releasable manner is the intravenous delivery line which may be connected to a patient.
In use when a high pressure dose of medicament is released into the second delivery chamber from the delivery device the pressure driving the dose out of the delivery device forces open the second pressure activated controlling means enabling the medicament to pass through the intravenous delivery line to the patient. However, when a low pressure dose enters the second dose chamber the energy driving the dose is insufficient to activate the second pressure activated controlling means. In such circumstances fluid returns to the reservoir via the a return tube to the reservoir.
Patient controlled delivery of medicaments that have a rapid action of onset may be delivered onto any dermal or mucosal surface that absorb medicaments quickly. Examples of surfaces that absorb medicaments quickly include the ocular surface, the respiratory tract, the nasal mucosa, the sublingual surface, the vaginal mucosa and the rectal mucosa. Preferably the route of delivery is dictated by the pharmokinetic properties of the medicament that is being delivered.
A typical intranasal medicament dose might be between 1 and 300 xcexcL while doses used for applying medicaments to skin or modified skin such as vagina or rectum may be significantly larger. The following represents a list of some of the medicaments which may be used with the apparatus of the present invention:
1. Drugs Affecting the Alimentary Tract
(i) H2 Receptor Antagonists: A large group of receptor H2 antagonists may be delivered intravenously to control symptoms. They may also be delivered hourly, they could also be delivered by intra-nasal delivery virtually as a constant infusion to control symptoms from ulcers. Examples include: Famotidine, Cimetidine and Ranitidine Hydrochloride.
(ii) Gastrointestinal tractxe2x80x94antispasmodics such as Hyoscine Butylbromide and Hyoscine Hydrobromide.
(iii) Cardiovascular medicaments such as Methyidopate HCl, Hydralazine hydrochloride, Clonidine hydrochloride, Verapamil, Glyceril Trinitrate, and Diazoxide and Sodium nitroprusside.
(iv) Cardiovascular medicamentsxe2x80x94Beta-adrenergic blocking agents such as: Esmolol hydrochloride, Propranolol HCl and Atenolol.
(v) Cardiovascular medicaments with diuretic effects such as Frusemide.
(vi) Cardiovascular medicamentsxe2x80x94anti-arrhythmic agents such as: Amiodarone hydrochloride, Verapamil hydrochloride, Procailnamide hydrochloride, Disopyramide, Flecainide acetate, and Lignocaine hydrochloride.
(vii) Cardiovascular medicamentsxe2x80x94anti-angina agents such as: Glyceryl trinitrate.
(viii) Cardio-ionatropic agents such as Digoxin
(ix) Adrenergic stimulants such as: Adrenalin, Metaraminol bitartrate, Dobutamine hydrochloride, Isoprenaline hydrochloride, Noradrenaline acid tartrate and Dopamine hydrochloride.
(x) Antimigraine preparations such as: Dihydroergotamine mesylate, and Sumatriptan succinate.
(xi) Other cardiovascular agents such as: Indomethacin.
2. Central Nervous System Medicaments
(i) Sedatives and Hypnotics such as: Chlormethiazole, Midazolam, Paraldehyde and Propofol.
(ii) Anti-anxiety agents such as: Diazepam, Droperidol, Chlorpromazine hydrochloride, Haloperidol decanoate, and Chlorpromazine hydrochloride.
3. Movement Disorders such as Benztropine mesylate, Phenytoin sodium, Phenobarbitone sodium and Clonazepam.
4. Narcotic Analgesics such as Fentanyl citrate, Sufentanyl, Alphentanyl, Morphine Sulphate, Pethidine hydrochloride, Phenoperidine hydrochloride, Papaveretum, Methadone hydrochloride and Buprenophine hydrochloride.
5. Non-steroidal Agents such as Indomethacin, Naproxen and Ketorolac trometamol.
6. Hormonal Preparations such Menopausal Gonadotrophin, Growth Hormonexe2x80x94Somatropin, Desmopressin acetate, Bromocriptine mesylate, Octreotide, Insulin, Glibenclamide, Mefformin hydrochloride, Glipizide and Tolbutamide.
7. Agents Acting on the Uterus such as: Oxytocin.
8. Prostaglandins such as Ritodrine hydrochloride and Salbutamol sulfate.
9. Bronchospasm Relaxants such as Aminophylline, Theophylline, Salbutamol sulfate, Orciprenaline sulfate, Ipratropium bromide, Fenoterol hydrobromide, Terbutaline sulfate and Adrenaline acid tartrate.
10. Other Peptides and Proteins.
The above list of medicaments that may be applied in a rate controlled manner using the present invention is not an exhaustive list. These are specific medicaments which may have maximum hourly infusion rates that need to be prescribed by a physician to maintain patient safety. Preferably any medicament that might be given by continuous intravenous infusion or by a patient controlled intravenous infusion can be potentially delivered using the present invention.
It will be understood that there may be modifications and changes to the present invention that will be apparent to one skilled in the art upon reading this specification. These modifications and changes are to be encompassed in the scope of the present invention.